Controlled Self-assembly Of Gold Porphyrin And Its Application In Photothermal/pH Double Response Synergistic Induction Chemotherapy

As the environment deteriorates,cancer has become one of the diseases with high morbidity and high mortality in recent years.In the face of cancer treatment problems,the current common treatment methods are the following:surgery,radiotherapy,chemotherapy,phototherapy and so on.Surgical treatment is mainly for early non-diffusing tumors,but it has great trauma to the human body;radiotherapy has high requirements for instruments and equipment,and there are major side effects;chemotherapy has high anticancer activity,simple treatment and other advantages,but there is specificity.Poor,it is difficult to accurately reach the cancer site and other shortcomings;phototherapy is an anti-cancer therapy developed in recent years,with the advantages of small trauma,low toxicity,good selectivity,short treatment time,and easy specific targeting.However,there are also problems of incomplete treatment caused by laser irradiation depth or uneven heating.At the same time,the transfer of cancer,the development of drug resistance,individual differences in cancer patients and other issues will also cause a single treatment mode to be ineffective for cancer treatment.Combination therapy can achieve a synergistic enhancement effect of1+1>2 by complementing the advantages of two or more treatment modes.Photothermal therapy can solve the problem of poor specificity and easy metabolism of small molecule drugs for chemotherapy;chemotherapeutic drugs can effectively eliminate tumor cells that are not completely treated by photothermal therapy;at the same time,photothermal is the preferred condition for intelligent external controlled release.A variety of complementary advantages have prompted the combination of photothermal therapy and chemotherapy to become a research hotspot for researchers.The combination of photothermal therapy and chemotherapy developed in recent years has excellent therapeutic effects,but these studies are usually carried out by blending photothermal materials,chemotherapeutic drugs,and stimuli-responsive materials,and the layer structure of the material structure is reduced.Problems such as photothermal performance,low loading rate of chemotherapeutic drugs,and cumbersome material synthesis steps.In order to solve these problems,we have investigated the structural molecular drugs with chemotherapeutic effects,and it is expected that the multifunctional treatment mode of photothermal and chemotherapy and the controlled release of tumor sites can be simultaneously realized by the construction of a single component.The results showed that gold porphyrin is a newly developed precious metal chemotherapeutic drug,which has superior chemotherapeutic activity and resistance to cisplatin,while the nanostructure of porphyrin has excellent photothermal effect,πconjugate of porphyrin.The macrocyclic structure combines with different substituents to achieve adjustable structural properties.Based on the above research background,this thesis mainly focuses on the synthesis of tetrapyridyl fund porphyrins;the controllable assembly of gold porphyrins;and the in vivo/in vitro synthesis of gold porphyrin nanospheres under acidic conditions.Release of multimodal combination therapy for photochemotherapy.The specific work is as follows:1.Develop a green,simple and efficient one-step hydrothermal method for the synthesis of gold porphyrin.The common synthetic routes of gold porphyrins are high temperature and organic phase,and the synthesis and purification processes are complicated and involve various toxic reagents（chloroform and N,N-dimethylformamide,etc.）.Starting from the tetrapyridylporphyrin（H₂TPyP）parent molecule,it is dissolved in hydrochloric acid solution,tetrapyridylporphyrin is protonated under acidic conditions,and then a 1:2 ratio of HAuCl₄ aqueous solution is added to adjust the appropriate concentration and temperature.And metallization reaction time,using the strong coordination of the inner ring pyrrole N and Au in the porphyrin center to realize the metallization of H₂TPyP,synthesize high-purity tetrapyridine fund porphyrin（AuTPyP）,and adopt UV-Vis,IR,Mass spectrometry and other means to characterize the successful preparation of tetrapyridine porphyrin,and the method was extended to other central metals,such as Cu,Co,Ni,Fe,Mn,Sn,In,Pd,etc.,which was successfully synthesized.No one has reported.2.The controlled assembly of AuTPyP was carried out by acid-base neutralization micelle limiting method and microemulsion assisted phase transfer method.Acid-base neutralization micelle limiting method The assembly of nanobelts,nanospheres,fusiform nanoparticles and nanorods can be obtained by adjusting the reaction conditions of different kinds of emulsifiers and pH values.The assembly of these AuTPyP assemblies Larger size is not suitable for use in cancer treatment.Microemulsion-assisted phase transfer method can control nano-microspheres with a uniform shape and uniform size of about 65 nm by regulating different emulsifier types and different volatilization times.The particle size of AuTPyP NPs and the enhanced absorption spectrum at 635 nm are suitable for photothermal therapy;fluorescence at 695nm can be applied to tumor fluorescence imaging at 488 nm;X-ray photoelectron spectroscopy results show stability of gold ions after assembly It can guarantee the smooth implementation of chemotherapy effect.3.After the surface modification of the bovine serum albumin component,an amino functional group is introduced on the surface of the AuTPyP NPs,and then the amino group is activated by EDC-NHS.Modification of cRGD targeting antibody,which allows the AuTPyP NPs@BSA-cRGD nano drug to specifically recognize and bind to integrin receptors highly expressed on the surface of tumor cell membranes,thereby greatly enhancing nanomedicine through integrin-mediated endocytosis and photothermal/chemotherapy Synergistic treatment efficiency.Then,in vitro and in vi vo photothermal/chemotherapy cascade synergistic therapy tests were performed to establish a HeLa subcutaneous tumor mouse model,and the biotoxicity,in vivo distribution,and heat/acid double of AuTPyP NPs@BSA-cRGD nanospheres were studied at the cell and animal levels,respectively.Stimulus response release efficiency and photothermal/chemotherapy synergistic treatment of tumors.